Genome Wide Association Study of Fetal Hemoglobin in Sickle Cell Anemia in Tanzania

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Abstract

Background

Fetal hemoglobin (HbF) is an important modulator of sickle cell disease (SCD). HbF has previously been shown to be affected by variants at three loci on chromosomes 2, 6 and 11, but it is likely that additional loci remain to be discovered.

Methods and Findings

We conducted a genome-wide association study (GWAS) in 1,213 SCA (HbSS/HbSβ ⁰) patients in Tanzania. Genotyping was done with Illumina Omni2.5 array and imputation using 1000 Genomes Phase I release data. Association with HbF was analysed using a linear mixed model to control for complex population structure within our study. We successfully replicated known associations for HbF near BCL11A and the HBS1L- MYB intergenic polymorphisms (HMIP), including multiple independent effects near BCL11A, consistent with previous reports. We observed eight additional associations with P<10 ⁻⁶. These associations could not be replicated in a SCA population in the UK.

Conclusions

This is the largest GWAS study in SCA in Africa. We have confirmed known associations and identified new genetic associations with HbF that require further replication in SCA populations in Africa.

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Most cited references 11

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Pain in sickle cell disease. Rates and risk factors.

O S Platt, B D Thorington, D Brambilla … (1991)

Acute episodes of pain are the principal symptom of sickle cell disease, but little is known about the epidemiologic features of these episodes or risk factors for them, nor is it known whether patients with high rates of such episodes die prematurely. We prospectively studied the natural history of sickle cell disease in 3578 patients ranging from newborns to persons up to 66 years old who were followed at clinical centers across the United States. There were 12,290 episodes of pain in 18,356 patient-years. The average rate was 0.8 episode per patient-year in sickle cell anemia, 1.0 episode per patient-year in sickle beta 0-thalassemia, and 0.4 episode per patient-year in hemoglobin SC disease and sickle beta(+)-thalassemia. The rate varied widely within each of these four groups--e.g., 39 percent of patients with sickle cell anemia had no episodes of pain, and 1 percent had more than six episodes per year. The 5.2 percent of patients with 3 to 10 episodes per year had 32.9 percent of all episodes. Among patients with sickle cell anemia who were more than 20 years old, those with high rates of pain episodes tended to die earlier than those with low rates. High rates were associated with a high hematocrit and low fetal hemoglobin levels. alpha-Thalassemia had no effect on pain apart from its association with an increased hematocrit. The "pain rate" (episodes per year) is a measure of clinical severity and correlates with early death in patients with sickle cell anemia over the age of 20. Even when the fetal hemoglobin level is low, one can predict that small increments in the level may have an ameliorating effect on the pain rate and may ultimately improve survival. This outcome is particularly encouraging to investigators studying hydroxyurea and other treatments designed to increase the fetal hemoglobin level.

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An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level.

Daniel E Bauer, Sophia C Kamran, Samuel Lessard … (2013)

Genome-wide association studies (GWASs) have ascertained numerous trait-associated common genetic variants, frequently localized to regulatory DNA. We found that common genetic variation at BCL11A associated with fetal hemoglobin (HbF) level lies in noncoding sequences decorated by an erythroid enhancer chromatin signature. Fine-mapping uncovers a motif-disrupting common variant associated with reduced transcription factor (TF) binding, modestly diminished BCL11A expression, and elevated HbF. The surrounding sequences function in vivo as a developmental stage-specific, lineage-restricted enhancer. Genome engineering reveals the enhancer is required in erythroid but not B-lymphoid cells for BCL11A expression. These findings illustrate how GWASs may expose functional variants of modest impact within causal elements essential for appropriate gene expression. We propose the GWAS-marked BCL11A enhancer represents an attractive target for therapeutic genome engineering for the β-hemoglobinopathies.

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Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia.

Manuela Uda, Renzo Galanello, Serena Sanna … (2008)

beta-Thalassemia and sickle cell disease both display a great deal of phenotypic heterogeneity, despite being generally thought of as simple Mendelian diseases. The reasons for this are not well understood, although the level of fetal hemoglobin (HbF) is one well characterized ameliorating factor in both of these conditions. To better understand the genetic basis of this heterogeneity, we carried out genome-wide scans with 362,129 common SNPs on 4,305 Sardinians to look for genetic linkage and association with HbF levels, as well as other red blood cell-related traits. Among major variants affecting HbF levels, SNP rs11886868 in the BCL11A gene was strongly associated with this trait (P < 10(-35)). The C allele frequency was significantly higher in Sardinian individuals with elevated HbF levels, detected by screening for beta-thalassemia, and patients with attenuated forms of beta-thalassemia vs. those with thalassemia major. We also show that the same BCL11A variant is strongly associated with HbF levels in a large cohort of sickle cell patients. These results indicate that BCL11A variants, by modulating HbF levels, act as an important ameliorating factor of the beta-thalassemia phenotype, and it is likely they could help ameliorate other hemoglobin disorders. We expect our findings will help to characterize the molecular mechanisms of fetal globin regulation and could eventually contribute to the development of new therapeutic approaches for beta-thalassemia and sickle cell anemia.

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Author and article information

Contributors

Yun Li: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 5 November 2014

Volume: 9

Issue: 11

Electronic Location Identifier: e111464

Affiliations

[1 ]Muhimbili Wellcome Programme, Department of Haematology and Blood Transfusion, Muhimbili University of Health and Allied Science, Dar-es-salaam, Tanzania

[2 ]Department of Biological Sciences, Dar es Salaam University College of Education, Dar-es-salaam, Tanzania

[3 ]Department of Human genetics, Wellcome Trust Sanger Institute, Cambridge, United Kingdom

[4 ]King’s College London, Department of Molecular Haematology, Division of Cancer Studies, London, United Kingdom

[5 ]National Institute for Medical Research, Tanga Centre, Tanga, Tanzania

[6 ]King’s College Hospital NHS Foundation Trust, Department of Haematological Medicine, London, United Kingdom

[7 ]MRC International Nutrition Group, Faculty of Epidemiology & Population Health, London School of Hygiene & Tropical Medicine, London, United Kingdom

[8 ]Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

University of North Carolina, United States of America

Author notes

* E-mail: siana.nkya@ 123456muhimbili-wellcome.org

Competing Interests: The authors have declared that no competing interests exit.

Conceived and designed the experiments: J. Makani SEC SM SLT JCB. Performed the experiments: SNM HR J. Mgaya SEC IK DS HM BM EM. Analyzed the data: JCB TS. Contributed to the writing of the manuscript: SNM TS J. Makani JCB SLT SEC.

¶ These authors are joint supervisors on this work

Article

Publisher ID: PONE-D-14-27886

DOI: 10.1371/journal.pone.0111464

PMC ID: 4221031

PubMed ID: 25372704

SO-VID: de96efe9-e283-4c54-b0f3-262809882958

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 25 June 2014

Date accepted : 19 September 2014

Page count

Pages: 8

Funding

The work was supported by the following: Wellcome Trust, UK (JCB 098051, J.Makani, SEC; strategic award 084538); and Commonwealth split-side fellowship, UK (SNM; TZCN-2012-361). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability The authors confirm that all data underlying the findings are fully available without restriction. All data are available at the European Genome-phenome Archive (EGA), accession number EGAS00001000990.

Genome Wide Association Study of Fetal Hemoglobin in Sickle Cell Anemia in Tanzania

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Abstract

Background

Methods and Findings

Conclusions

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Most cited references 11

Pain in sickle cell disease. Rates and risk factors.

An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level.

Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia.

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